Biology:AKT1

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


RAC(Rho family)-alpha serine/threonine-protein kinase is an enzyme that in humans is encoded by the AKT1 gene. This enzyme belongs to the AKT subfamily of serine/threonine kinases that contain SH2 (Src homology 2-like) protein domains.[1] It is commonly referred to as PKB, or by both names as "Akt/PKB".

Function

The serine-threonine protein kinase AKT1 is catalytically inactive in serum-starved primary and immortalized fibroblasts. AKT1 and the related AKT2 are activated by platelet-derived growth factor. The activation is rapid and specific, and it is abrogated by mutations in the pleckstrin homology domain of AKT1. It was shown that the activation occurs through phosphatidylinositol 3-kinase. In the developing nervous system AKT is a critical mediator of growth factor-induced neuronal survival. Survival factors can suppress apoptosis in a transcription-independent manner by activating the serine/threonine kinase AKT1, which then phosphorylates and inactivates components of the apoptotic machinery. Mice lacking Akt1 display a 25% reduction in body mass, indicating that Akt1 is critical for transmitting growth-promoting signals, most likely via the IGF1 receptor. Mice lacking Akt1 are also resistant to cancer: They experience considerable delay in tumor growth initiated by the large T antigen or the Neu oncogene. A single-nucleotide polymorphism in this gene causes Proteus syndrome.[2][3]

History

AKT (now also called AKT1) was originally identified as the oncogene in the transforming retrovirus, AKT8.[4] AKT8 was isolated from a spontaneous thymoma cell line derived from AKR mice by cocultivation with an indicator mink cell line. The transforming cellular sequences, v-akt, were cloned from a transformed mink cell clone and these sequences were used to identify Akt1 and Akt2 in a human clone library. AKT8 was isolated by Stephen Staal in the laboratory of Wallace P. Rowe; he subsequently cloned v-akt and human AKT1 and AKT2 while on staff at the Johns Hopkins Oncology Center.[5]

In 2011, a mutation in AKT1 was strongly associated with Proteus syndrome, the disease that probably affected the Elephant Man.[6]

The name Akt stands for Ak strain transforming. The origins of the Akt name date back to 1928, when J. Furth performed experimental studies on mice that developed spontaneous thymic lymphomas. Mice from three different stocks were studied, and the stocks were designated A, R, and S. Stock A was noted to yield many cancers, and inbred families were subsequently designated by a second small letter (Aa, Ab, Ac, etc.), and thus came the Ak strain of mice. Further inbreeding was undertaken with Ak mice at the Rockefeller Institute in 1936, leading to the designation of the AKR mouse strain. In 1977, a transforming retrovirus was isolated from the AKR mouse. This virus was named Akt-8, the "t" representing its transforming capabilities.

Interactions

AKT1 has been shown to interact with:

See also

  • AKT – the AKT family of proteins
  • AKT2 – the gene for the second member of the AKT family
  • AKT3 – the gene for the third member of the AKT family
  • Proteus syndrome

References

  1. ↑ "Entrez Gene: AKT1 v-akt murine thymoma viral oncogene homolog 1". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=207. 
  2. ↑ "A mosaic activating mutation in AKT1 associated with the Proteus syndrome". N. Engl. J. Med. 365 (7): 611–9. 2011. doi:10.1056/NEJMoa1104017. PMID 21793738. 
  3. ↑ Cohen MM (2014). "Proteus syndrome review: molecular, clinical, and pathologic features". Clin. Genet. 85 (2): 111–9. doi:10.1111/cge.12266. PMID 23992099. 
  4. ↑ "Isolation of transforming murine leukemia viruses from mice with a high incidence of spontaneous lymphoma". Proc. Natl. Acad. Sci. U.S.A. 74 (7): 3065–7. July 1977. doi:10.1073/pnas.74.7.3065. PMID 197531. Bibcode: 1977PNAS...74.3065S. 
  5. ↑ Staal SP (July 1987). "Molecular cloning of the akt oncogene and its human homologues AKT1 and AKT2: amplification of AKT1 in a primary human gastric adenocarcinoma". Proc. Natl. Acad. Sci. U.S.A. 84 (14): 5034–7. doi:10.1073/pnas.84.14.5034. PMID 3037531. Bibcode: 1987PNAS...84.5034S. 
  6. ↑ "A Mosaic Activating Mutation in Associated with the Proteus Syndrome". New England Journal of Medicine 365 (7): 611–619. 27 July 2011. doi:10.1056/NEJMoa1104017. PMID 21793738. 
  7. ↑ "Regulation of apoptosis by the Ft1 protein, a new modulator of protein kinase B/Akt". Mol. Cell. Biol. 24 (4): 1493–504. Feb 2004. doi:10.1128/mcb.24.4.1493-1504.2004. PMID 14749367. 
  8. ↑ "Negative regulation of the serine/threonine kinase B-Raf by Akt". J. Biol. Chem. 275 (35): 27354–9. Sep 2000. doi:10.1074/jbc.M004371200. PMID 10869359. 
  9. ↑ "Heregulin induces phosphorylation of BRCA1 through phosphatidylinositol 3-Kinase/AKT in breast cancer cells". J. Biol. Chem. 274 (45): 32274–8. Nov 1999. doi:10.1074/jbc.274.45.32274. PMID 10542266. 
  10. ↑ "Negative Regulation of AKT Activation by BRCA1". Cancer Res. 68 (24): 10040–4. Dec 2008. doi:10.1158/0008-5472.CAN-08-3009. PMID 19074868. 
  11. ↑ "Phosphorylation and regulation of Raf by Akt (protein kinase B)". Science 286 (5445): 1741–4. Nov 1999. doi:10.1126/science.286.5445.1741. PMID 10576742. 
  12. ↑ "Akt-dependent phosphorylation of p27Kip1 promotes binding to 14-3-3 and cytoplasmic localization". J. Biol. Chem. 277 (32): 28706–13. Aug 2002. doi:10.1074/jbc.M203668200. PMID 12042314. 
  13. ↑ "NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase". Nature 401 (6748): 82–5. Sep 1999. doi:10.1038/43466. PMID 10485710. Bibcode: 1999Natur.401...82N. 
  14. ↑ "NF-kappaB is a target of AKT in anti-apoptotic PDGF signalling". Nature 401 (6748): 86–90. Sep 1999. doi:10.1038/43474. PMID 10485711. Bibcode: 1999Natur.401...86R. 
  15. ↑ "PKB-mediated negative feedback tightly regulates mitogenic signalling via Gab2". EMBO J. 21 (1–2): 72–82. Jan 2002. doi:10.1093/emboj/21.1.72. PMID 11782427. 
  16. ↑ "Regulation of telomerase activity and anti-apoptotic function by protein-protein interaction and phosphorylation". FEBS Lett. 536 (1–3): 180–6. Feb 2003. doi:10.1016/s0014-5793(03)00058-9. PMID 12586360. 
  17. ↑ "IL-2 increases human telomerase reverse transcriptase activity transcriptionally and posttranslationally through phosphatidylinositol 3'-kinase/Akt, heat shock protein 90, and mammalian target of rapamycin in transformed NK cells". J. Immunol. 174 (9): 5261–9. May 2005. doi:10.4049/jimmunol.174.9.5261. PMID 15843522. 
  18. ↑ "Modulation of Akt kinase activity by binding to Hsp90". Proc. Natl. Acad. Sci. U.S.A. 97 (20): 10832–7. Sep 2000. doi:10.1073/pnas.170276797. PMID 10995457. Bibcode: 2000PNAS...9710832S. 
  19. ↑ 19.0 19.1 "Protein kinase B is regulated in platelets by the collagen receptor glycoprotein VI". J. Biol. Chem. 277 (15): 12874–8. Apr 2002. doi:10.1074/jbc.M200482200. PMID 11825911. 
  20. ↑ 20.0 20.1 "Regulation of protein kinase B/Akt-serine 473 phosphorylation by integrin-linked kinase: critical roles for kinase activity and amino acids arginine 211 and serine 343". J. Biol. Chem. 276 (29): 27462–9. Jul 2001. doi:10.1074/jbc.M102940200. PMID 11313365. 
  21. ↑ "Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/AKT by the integrin-linked kinase". Proc. Natl. Acad. Sci. U.S.A. 95 (19): 11211–6. Sep 1998. doi:10.1073/pnas.95.19.11211. PMID 9736715. Bibcode: 1998PNAS...9511211D. 
  22. ↑ "Inhibition of protein kinase B (PKB) and PKCzeta mediates keratin K10-induced cell cycle arrest". Mol. Cell. Biol. 21 (21): 7449–59. Nov 2001. doi:10.1128/MCB.21.21.7449-7459.2001. PMID 11585925. 
  23. ↑ "Akt (protein kinase B) negatively regulates SEK1 by means of protein phosphorylation". J. Biol. Chem. 277 (4): 2573–8. Jan 2002. doi:10.1074/jbc.M110299200. PMID 11707464. 
  24. ↑ "Negative regulation of mixed lineage kinase 3 by protein kinase B/AKT leads to cell survival". J. Biol. Chem. 278 (6): 3897–902. Feb 2003. doi:10.1074/jbc.M211598200. PMID 12458207. 
  25. ↑ "Akt-dependent phosphorylation specifically regulates Cot induction of NF-kappa B-dependent transcription". Mol. Cell. Biol. 22 (16): 5962–74. Aug 2002. doi:10.1128/mcb.22.16.5962-5974.2002. PMID 12138205. 
  26. ↑ 26.0 26.1 "p38 Kinase-dependent MAPKAPK-2 activation functions as 3-phosphoinositide-dependent kinase-2 for Akt in human neutrophils". J. Biol. Chem. 276 (5): 3517–23. Feb 2001. doi:10.1074/jbc.M005953200. PMID 11042204. 
  27. ↑ "Akt and CHIP coregulate tau degradation through coordinated interactions". Proc. Natl. Acad. Sci. U.S.A. 105 (9): 3622–7. Mar 2008. doi:10.1073/pnas.0709180105. PMID 18292230. Bibcode: 2008PNAS..105.3622D. 
  28. ↑ 28.0 28.1 "Differential regulation of Akt kinase isoforms by the members of the TCL1 oncogene family". J. Biol. Chem. 277 (5): 3743–51. Feb 2002. doi:10.1074/jbc.M107069200. PMID 11707444. 
  29. ↑ 29.0 29.1 "The protooncogene TCL1 is an Akt kinase coactivator". Mol. Cell 6 (2): 395–407. Aug 2000. doi:10.1016/S1097-2765(00)00039-3. PMID 10983986. 
  30. ↑ "Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex". Science 307 (5712): 1098–101. Feb 2005. doi:10.1126/science.1106148. PMID 15718470. Bibcode: 2005Sci...307.1098S. 
  31. ↑ "A direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin in mitogen-stimulated and transformed cells". Cancer Res. 60 (13): 3504–13. Jul 2000. PMID 10910062. 
  32. ↑ "Thr2446 is a novel mammalian target of rapamycin (mTOR) phosphorylation site regulated by nutrient status". J. Biol. Chem. 279 (16): 15719–22. Apr 2004. doi:10.1074/jbc.C300534200. PMID 14970221. 
  33. ↑ "Nuclear Akt interacts with B23/NPM and protects it from proteolytic cleavage, enhancing cell survival". Proc. Natl. Acad. Sci. U.S.A. 105 (43): 16584–9. Oct 2008. doi:10.1073/pnas.0807668105. PMID 18931307. Bibcode: 2008PNAS..10516584L. 
  34. ↑ "Akt phosphorylates and regulates the orphan nuclear receptor Nur77". Proc. Natl. Acad. Sci. U.S.A. 98 (7): 3690–4. Mar 2001. doi:10.1073/pnas.051003198. PMID 11274386. Bibcode: 2001PNAS...98.3690P. 
  35. ↑ "Akt suppresses androgen-induced apoptosis by phosphorylating and inhibiting androgen receptor". Proc. Natl. Acad. Sci. U.S.A. 98 (13): 7200–5. Jun 2001. doi:10.1073/pnas.121173298. PMID 11404460. Bibcode: 2001PNAS...98.7200L. 
  36. ↑ "Inhibition of Akt and its anti-apoptotic activities by tumor necrosis factor-induced protein kinase C-related kinase 2 (PRK2) cleavage". J. Biol. Chem. 275 (44): 34451–8. Nov 2000. doi:10.1074/jbc.M001753200. PMID 10926925. 
  37. ↑ "Complex formation and cooperation of protein kinase C theta and Akt1/protein kinase B alpha in the NF-kappa B transactivation cascade in Jurkat T cells". J. Biol. Chem. 276 (34): 31627–34. Aug 2001. doi:10.1074/jbc.M103098200. PMID 11410591. 
  38. ↑ "The activity of the plexin-A1 receptor is regulated by Rac". J. Biol. Chem. 279 (32): 33199–205. Aug 2004. doi:10.1074/jbc.M402943200. PMID 15187088. 
  39. ↑ "A modeled hydrophobic domain on the TCL1 oncoprotein mediates association with AKT at the cytoplasmic membrane". Biochemistry 41 (20): 6376–82. May 2002. doi:10.1021/bi016068o. PMID 12009899. 
  40. ↑ "TRB3: a tribbles homolog that inhibits Akt/PKB activation by insulin in liver". Science 300 (5625): 1574–7. Jun 2003. doi:10.1126/science.1079817. PMID 12791994. Bibcode: 2003Sci...300.1574D. 
  41. ↑ 41.0 41.1 "Phosphatidylinositol 3-kinase/Akt pathway regulates tuberous sclerosis tumor suppressor complex by phosphorylation of tuberin". J. Biol. Chem. 277 (38): 35364–70. Sep 2002. doi:10.1074/jbc.M205838200. PMID 12167664. 
  42. ↑ 42.0 42.1 "Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase". Proc. Natl. Acad. Sci. U.S.A. 101 (37): 13489–94. Sep 2004. doi:10.1073/pnas.0405659101. PMID 15342917. Bibcode: 2004PNAS..10113489R. 
  43. ↑ "Identification of 14-3-3zeta as a protein kinase B/Akt substrate". J. Biol. Chem. 277 (24): 21639–42. Jun 2002. doi:10.1074/jbc.M203167200. PMID 11956222. 

Further reading

External links



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